Neuronal activity triggers endocytosis at synaptic terminals to retrieve efficiently the exocytosed vesicle membrane, ensuring the membrane homeostasis of active zones and the continuous supply of releasable vesicles. The kinetics of endocytosis depends on Ca2+ and calmodulin which, as a versatile signal pathway, can activate a broad spectrum of downstream targets, including myosin light chain kinase (MLCK). MLCK is known to regulate vesicle trafficking and synaptic transmission, but whether this kinase regulates vesicle endocytosis at synapses remains elusive. We investigated this issue at the rat calyx of Held synapse, where previous studies using whole-cell membrane capacitance measurement have characterized two common forms of Ca2+/calmodulin-dependent endocytosis, i.e., slow clathrin-dependent endocytosis and rapid endocytosis. Acute inhibition of MLCK with pharmacological agents was found to slow down the kinetics of both slow and rapid forms of endocytosis at calyces. Similar impairment of endocytos...

There is evidence that i.c.v. infusion of the â-amyloid (Aâ) 1-42 peptide fragment (BAP 1-42) may cause brain dysfunction as evidenced by neurodegeneration and impairment of learning and memory, typical symptoms of Alzheimer’s disease. Neurodegeneration affects subcortical nuclei involved in cognitive behavior and disrupt cholinergic neurotransmission in these nuclei. Endogenous cannabinoids decrease brain ACh levels and may induce a deficit of memory capacity. These effects are mediated by the activation of CB1 cannabinoid receptors. In fact, administration of the selective CB1 cannabinoid receptor antagonist, SR141716A, reversed in mice the cognitive impairment induced by cannabinoids, such as marijuana and its active ingredient Ä9 – tetrahydrocannabinol, or endogenous cannabinoids, such as anandamide. SR141716A also counteracted the amnesia induced by BAP 1-42 in the passive avoidance paradigm. It is likely that a direct correlation exists between the amnesic effect induced by Aâ and cerebral CB1 action...

Activation of cannabinoid CB1 receptors reduces glutamatergic synaptic transmission in the rodent striatum and is involved in the normal control of motor function by the basal ganglia. Here we investigated CB1 receptor regulation of glutamate release and uptake and synaptic transmission in the rat striatum. We show that CB1 receptor activation reduces both the release and uptake of [3H]glutamate in striatal slices. We also demonstrate that both activation of CB1 receptors and inhibition of glutamate uptake reduce corticostriatal synaptic transmission in a mutually occlusive manner and that both forms of depression are dependent on metabotropic glutamate receptor (mGluR) activation. We propose that CB1 receptor activation in the striatum decreases glutamate transporter activity and that the resulting increase in synaptic cleft glutamate concentration causes the activation of presynaptic mGluRs, which then decrease glutamate release.

The ventral tegmental area (VTA) in the midbrain modulates reward processing. Drugs of abuse can increase midbrain dopamine (DA) activity, and can alter VTA glutamate plasticity, leading to addiction. While DA neurons are the principal mediator of rewar...

Feeding behavior is one of most important motivated behaviors and the most potent drive for feeding is its reward nature in human and mammal. The lateral hypothalamus is critical for regulation of feeding behavior and is considered an important structure for the brain reward circuitry. Synaptic interactions within the hypothalamus per se as well as the activity of the feeding-related projection neurons in the lateral hypothalamus are subject to extensive modulation. Despite the well-known physiological effects of nicotine and delta9(-)-tetrahydrocannabinol (THC) administered exogenously, relatively little is known of the hypothalamic actions of their endogenous counterparts. Our present study provided a neurophysiological analysis of the modulation of the excitability of melanin-concentrating hormone (MCH) synthesizing neurons in the lateral hypothalamus (LH) implicated in natural reward behavior. We first identified MCH neurons based on the electrophysiological profile. MCH neurons showed a strong accommo...

In recent years, the pervasiveness of the opioid crisis has underscored the urgent need to identify novel compounds that circumvent opioid abuse liability while sparing their therapeutic efficacy. Opioid reward and reinforcement require crosstalk betwee...

The mechanism of tau aggregates causing neuronal dysfunction and neuronal loss in tauopathy patients is still controversial. We previously reported that in Alzheimer’s disease (AD), tau aggregation induces mislocalization and coaggregation of DNA repair...

Cannabis (i.e., marijuana and cannabinoids) is the most commonly used illicit drug in developed countries, and the lifetime prevalence of marijuana dependence is the highest of all illicit drugs in the United States. To provide clues for finding effective pharmacological treatment for cannabis-dependent patients, we examined the effects and possible mechanism of lithium administration on the cannabinoid withdrawal syndrome in rats. A systemic injection of the mood stabilizer lithium, at serum levels that were clinically relevant, prevented the cannabinoid withdrawal syndrome. The effects of lithium were accompanied by expression of the cellular activation marker Fos proteins within most oxytocin-immunoreactive neurons and a significant increase in oxytocin mRNA expression in the hypothalamic paraventricular and supraoptic nuclei. Lithium also produced a significant elevation of oxytocin levels in the peripheral blood. We suggest that the effects of lithium against the cannabinoid withdrawal syndrome are m...

Consumers of marijuana feel a strong compulsive desire to consume food. The role of CB2 receptors in food and alcohol consumption and the behavioral effects of CB2 receptor ligands are not well understood. We tested the effects of CB2 agonist PEA and CB...

Neuroprotective effects have been described for many cannabinoids in several neurotoxicity models. However, the exact mechanisms have not been clearly understood yet. In the present study, antioxidant neuroprotective effects of cannabinoids and the involvement of the cannabinoid receptor 1 (CB1) were analyzed employing cell-free biochemical assays and cultured cells. As it was reported for estrogens that the phenolic group is a lead structure for antioxidant neuroprotective effects, the nine compounds tested were classified into three groups. Group A: phenolic compounds not binding to CB1 (cannabinol, cannabidiol, AM 404). Group B: non-phenolic compounds binding to CB1 (methanandamide, WIN 55,212-2, SR 141716A). Group C: phenolic compounds binding to CB1 (D9-THC, CP 55,940, HU 210). In the biochemical assays employed, a requirement of the phenolic lead structure for antioxidant activity was shown. The effects paralleled the protective potential of group A and C compounds in oxidative neuronal cell death us...